Dear Editor, The G protein-coupled receptor GPR139 is involved in neuro-modulation,and one of its agonists is in clinical trials for the treatment of cognitive impairment and negative symptoms of schizophrenia.While GPR139 is a understudied 'orphan'receptor,it can be activated by the amino acids L-Trp,L-Phe1 or α-Melanocyte-stimulating hormone (α-MSH) which is an endogenous agonist of melanocortin receptors.2,3 GPR139 activation triggers4-7 several G protein pathways of which Gq/11 is the primary.Of note,the expression of GPR139 correlates with that of the μ-opioid and dopamine D2 receptors in a broad range of the central nervous system (CNS),which acts as a regulator of μ-opioid and dopamine signaling.6-9 For example,GPR139 antagonist JNJ-3792165 increases the sensitivity of the μ-opioid receptor to morphine.6 Hitherto,the structural basis of how ligands interact with and activate GPR139 to transduce diverse signals has remained unknown.Furthermore,the more physiologically relevant inter-mediate states of GPCR-G protein complex structures in the nucleotide-bound forms are also elusive.Here,we report the cryo-electron microscopy (cryo-EM) structures of GPR139 in complex with a key reference ligand JNJ-63533054 which is an analog of agent TAK-04110 in clinical trial,and miniGs/q or Gi in nucleotide-free form,as well as the GPR139-JNJ-63533054-miniGs/q complex in GDP-and GTP-bound states,respectively (Fig.1a-f).

Yali Zhou;Henrik Daver;Boris Trapkov;Lijie Wu;Meng Wu;Kasper Harps?e;Patrick R.Gentry;Kaiwen Liu;Marina Larionova;Junlin Liu;Na Chen;Hans Br(a)uner-Osborne;David E.Gloriam;Tian Hua;Zhi-Jie Liu

iHuman Institute,ShanghaiTech University,Shanghai,China;School of Life Science and Technology,ShanghaiTech University,Shanghai,China;University of Chinese Academy of Sciences,Beijing,China;CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai,China;Department of Drug Design and Pharmacology,University of Copenhagen,Universitetsparken 2,Copenhagen,Denmark;Photobiology laboratory,Institute of Biophysics SB RAS,Federal Research Center "Krasnoyarsk Science Center SB RAS",Akademgorodok 50/50,Krasnoyarsk,Russia

细胞研究（英文版）

[1]Yali Zhou;Henrik Daver;Boris Trapkov;Lijie Wu;Meng Wu;Kasper Harps?e;Patrick R.Gentry;Kaiwen Liu;Marina Larionova;Junlin Liu;Na Chen;Hans Br(a)uner-Osborne;David E.Gloriam;Tian Hua;Zhi-Jie Liu-.Molecular insights into ligand recognition and G protein coupling of the neuromodulatory orphan receptor GPR139)[J].细胞研究（英文版）,2022(02):210-213

neuromodulatory,GPR139,Phe1,Melanocyte,triggers4,miniGs

Molecular,insights,into,recognition,protein,coupling,orphan,Dear,Editor, The,coupled,involved,modulation,its,agonists,clinical,trials,treatment,cognitive,impairment,negative,symptoms,schizophrenia,While,understudied,can,be,activated,by,amino,acids,Trp,stimulating,hormone,MSH,which,endogenous,melanocortin,receptors,activation,several,pathways,Gq,primary,Of,note,expression,correlates,that,opioid,dopamine,D2,broad,range,central,nervous,system,CNS,acts,regulator,signaling,For,example,antagonist,JNJ,increases,sensitivity,morphine,Hitherto,structural,basis,how,ligands,interact,transduce,diverse,signals,has,remained,unknown,Furthermore,physiologically,relevant,mediate,states,GPCR,complex,structures,nucleotide,bound,forms,are,also,elusive,Here,report,cryo,electron,microscopy,EM,key,reference,analog,agent,TAK,Gi,free,well,GTP,respectively,Fig,1a

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